SERT polymorphisms and human cortical 5-HT2A receptors

描述（由申请人提供）：神经递质5-羟色胺（5-HT）参与多种脑功能，包括医学和精神疾病。编码5-HT转运体的基因启动子区域的常见变异[5-HT；SERT)与转运蛋白功能表达的改变有关。具体来说，该区域的44个碱基对缺失多态性（简称S）导致转运蛋白表达减少，而该区域的44个碱基对插入多态性（简称L）导致转运蛋白表达减少。新出现的证据表明，该系统实际上是三等位基因，体外5-HTT （SERT）表达水平最高的是L-A L-A纯合子。一些报告已经确定了特定等位基因模式与精神疾病之间的联系，包括压力相关的抑郁症。此外，5-HTTLPR变异的强大效应已经通过大脑区域激活试验得到证实。然而，5-HTT （SERT）表达改变与压力相关性抑郁和脑功能改变之间的联系机制尚不清楚。5-羟色胺在大脑中的作用表明突触5-羟色胺信号传导的改变可能具有神经发育和持续的结构和神经生理效应。由于5-HTT （SERT）是5-羟色胺能信号传导持续时间的调节因子之一，轴突末端5-HTT （SERT）的功能表达水平较低（在SS纯合子中发现）预示着突触后脑5-羟色胺能受体的持续激动剂作用。虽然各种可能将5-HTTLPR多态性与精神疾病和脑功能联系起来的候选机制需要研究，但作为我们的主要目的，我们选择使用使用5-HT受体配体[18 F] setoperone的正电子发射断层扫描（PET）来检查健康女性受试者皮质5-HT2A受体的状态，该受体纯合为5-HTT启动子区域多态性的SS或L-A L-A等位基因。作为次要目标，我们建议对影响5-HT2A表达的常见单核苷酸多态性（SNP） forT102C进行基因分型，并使用基于体素的形态测定（VBM）方法通过基因型检测区域脑容量，检测5-HTTLPR的潜在脑容量效应。由于女性抑郁率高于男性，并且5-HT2A受体的调节受雌激素的影响，我们选择研究SS或L-A L-A基因型对女性受试者的影响。

DESCRIPTION (provided by applicant): The neurotransmitter serotonin (5-HT) is involved in a wide variety of brain functions including medical and psychiatric illnesses. Common variations in the promoter region of the gene encoding the 5-HT transporter [5-HTT; SERT) are associated with altered functional expression of the transporter. Specifically, a well- established 44 base pair deletion polymorphism in this region (termed S, for short) leads to reduced expression of transporter versus a 44 base pair insertion polymorphism in this region (termed L, for long). Emerging evidence suggests that this system is actually tri-allelic, with highest levels of in vitro 5-HTT (SERT) expression present in the L-A L-A homozygote. Several reports have identified associations between a given allele pattern and psychiatric conditions, including stress-associated depression. Further, robust effects of variations in the 5-HTTLPR have been demonstrated with assays of regional brain activation. However, the mechanism through which altered 5-HTT (SERT) expression is linked to stress-associated depression and altered brain function is unknown. The actions of 5-HT in the brain suggest that altered synaptic 5-HT signaling could have neurodevelopmental and ongoing structural and neurophysiological effects. Because the 5-HTT (SERT) is one regulator of the duration of serotonergic signaling, lower levels of functional expression of the axon terminal 5-HTT (SERT) (as found in the SS homozygote) predict sustained agonist effects at post-synaptic brain serotonergic receptors. While a variety of candidate mechanisms potentially linking 5-HTTLPR polymorphisms to psychiatric illness and brain function require investigation, as our primary Aim, we have chosen to use positron emission tomography (PET) employing the 5-HT receptor ligand [18 F] setoperone to examine the status of cortical 5-HT2A receptors in healthy female subjects homozygous for the SS or L-A L-A alleles of the 5-HTT promoter region polymorphism. As a secondary aims, we propose to additionally perform genotyping forT102C, a common single nucleotide polymorphism (SNP) affecting 5-HT2A expression and to examine potential brain volumetric effects of the 5-HTTLPR using the voxel-based morphometry (VBM) method to examine regional brain volume by genotype. Because the rate of depression is greater in females than males, and because regulation of the 5-HT2A receptor is influenced by estrogen, we have chosen to study the effects of having SS or L-A L-A genotype in female subjects.